13-39655706-G-GC

Variant names:

• chr13-39655706-G-GC
• rs746938820
• NM_020751.3:c.-21_-20insC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_020751.3(COG6):​c.-21_-20insC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,486,174 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: COG6 NM_020751.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.32
• Publications: 0 publications found

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

COG6 Gene-Disease associations (from GenCC):

• COG6-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 13-39655706-G-GC is Benign according to our data. Variant chr13-39655706-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312126.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000925 (51/55146) while in subpopulation EAS AF = 0.0069 (11/1594). AF 95% confidence interval is 0.00387. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.-21_-20insC		5_prime_UTR_variant	Exon 1 of 19	ENST00000455146.8	NP_065802.1
COG6	NR_026745.1	n.80_81insC		non_coding_transcript_exon_variant	Exon 1 of 20
COG6	NM_001145079.2	c.-21_-20insC		5_prime_UTR_variant	Exon 1 of 19		NP_001138551.1
COG6	XM_011535168.2	c.-21_-20insC		5_prime_UTR_variant	Exon 1 of 20		XP_011533470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.-21_-20insC		5_prime_UTR_variant	Exon 1 of 19	1	NM_020751.3	ENSP00000397441.2

Frequencies

GnomAD3 genomes AF: 0.000944 AC: 52 AN: 55088 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00689

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000155

Gnomad OTH AF: 0.00154

GnomAD2 exomes AF: 0.000586 AC: 35 AN: 59716 AF XY: 0.000490

Gnomad AFR exome AF: 0.00232

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.000645

GnomAD4 exome AF: 0.000217 AC: 310 AN: 1431028 Hom.: 1 Cov.: 40 AF XY: 0.000231 AC XY: 164 AN XY: 709170

African (AFR) AF: 0.000765 AC: 25 AN: 32688

American (AMR) AF: 0.000191 AC: 8 AN: 41854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00617 AC: 234 AN: 37896

South Asian (SAS) AF: 0.00 AC: 0 AN: 82694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.0000338 AC: 37 AN: 1095584

Other (OTH) AF: 0.000102 AC: 6 AN: 59002

GnomAD4 genome AF: 0.000925 AC: 51 AN: 55146 Hom.: 0 Cov.: 34 AF XY: 0.000977 AC XY: 26 AN XY: 26600

African (AFR) AF: 0.00167 AC: 29 AN: 17388

American (AMR) AF: 0.00208 AC: 6 AN: 2884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1052

East Asian (EAS) AF: 0.00690 AC: 11 AN: 1594

South Asian (SAS) AF: 0.00 AC: 0 AN: 1154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.000155 AC: 4 AN: 25796

Other (OTH) AF: 0.00155 AC: 1 AN: 646

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.00141 AC: 3 AN: 2142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital disorder of glycosylation Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 22, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

COG6-related disorder Benign:1

Feb 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.3
Mutation Taster		=296/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746938820; hg19: chr13-40229843;